Clinical Trial: The Role of Endothelin-1 in Sickle Cell Disease

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: The Role of Endothelin-1 in Sickle Cell Disease

Brief Summary: The primary goal of the study is to determine the safety and tolerability of ambrisentan. It is also expected that ambrisentan will improve blood flow in the lungs, decrease inflammation, and reduce pain in sickle cell patients. An additional goal is to evaluate the use of select biomarkers in evaluating sickle nephropathy.

Detailed Summary:

The purpose of this study is to test the hypothesis that endothelin antagonist (ETA) receptor blockade using ambrisentan is safe, tolerable, and improves kidney function/albuminuria in patients with sickle cell disease (SCD). The investigators anticipate a reduction in proteinuria, a decrease in tricuspid regurgitation jet (TRJ) velocity, reduction in inflammatory markers, improvement in forearm blood flow, and improvement in nociception/pain.

The primary efficacy endpoint was chosen as the effect of ETA receptor blockade on the reduction of microalbuminuria based upon findings in diabetic nephropathy, which has a similar pathogenesis to sickle nephropathy. A 30% reduction in proteinuria is rather conservative and realistic based upon the results of studies of ETA receptor blockade in diabetic nephropathy that consistently resulted in 40-45% reduction in proteinuria. Pre-clinical data has shown that changes can be detected in urinary nephrin excretion before overt proteinuria is observed in a model of chronic ET-1 elevation. Furthermore, tubular injury that can occur as a result of an intrarenal vaso-occlusive crisis (VOC) should be expected to increase the level of renal tubular injury markers, neutrophil gelantinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and netrin. Treatment with ambrisentan would be expected to attenuate these changes. Dr. Jennifer Pollock, has extensive experience with all of the biomarker assays including ET-1. Dr. Pollock runs bio-analytical core labs for two PO1s and has published extensively on these and similar methods in human and animal samples.

Additional rationale for this project is based on recent 24-hour urine results for creatinine clearance and total protein excretion from 97 patients with sickle cell anemia (Hb SS) and sickle beta zero thalassemia (SB0-thalassemi
Sponsor: Augusta University

Current Primary Outcome: Safety and Tolerability of ambrisentan in patients with sickle cell disease measured by physical exam, vital signs, blood and urine testing, ECG (specified visits), concomitant medication review, adverse events review [ Time Frame: Day 1 (Baseline) through Day 113 ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Efficacy of ambrisentan in improving kidney function in patients with sickle cell disease measured by blood [ Time Frame: Day 1 (Baseline), Day 15, Day 29, Day 57, Day 85, and Day 113 ]
  measured by blood
• Efficacy of ambrisentan in decreasing TRJ velocity [ Time Frame: Day 1 (Baseline) and at the end of the 12 week treatment period ]
  measured by echocardiogram
• Efficacy of ambrisentan in decreasing inflammation [ Time Frame: Day 1 (Baseline) through Day 113 ]
  measurement of inflammatory markers in blood
• Efficacy of ambrisentan in improving micro-circulation [ Time Frame: Day 1 (Baseline) and at the end of the 12 week treatment period ]
  measured by forearm and skin blood flow measurements
• Efficacy of ambrisentan in improving macro-circulation [ Time Frame: Day 1 (Baseline), and at the end of the 12 week treatment period ]
  measured by Transcranial Doppler (TCD)
• Efficacy of ambrisentan in improving nociception/pain [ Time Frame: Day 1 (Baseline), and at the end of the 12 week treatment period ]
  performance of quantitative sensory testing
• Efficacy of ambrisentan in improving kidney function in patients with sickle cell disease measured by urine testing for microalbuminuria/proteinuria [ Time Frame: Day 1 (Baseline), Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, and Day 113 ]
  measured by urine testing for microalbuminuria/proteinuria
• Efficacy of ambrisentan in improving nociception/pain [ Time Frame: Day 1 (Baseline), and at the end of the 12 week treatment period ]
  assessment of pain diaries/questionnaires
• Efficacy of ambrisentan in improving nociception/pain [ Time Frame: Day 1 (Baseline) through the 12 week treatment period ]
  assessment of adverse events

Original Secondary Outcome: Same as current

Information By: Augusta University

Dates:
Date Received: October 2, 2015
Date Started: September 2015
Date Completion: May 2018
Last Updated: June 21, 2016
Last Verified: June 2016